Obesity leads to high cardiovascular morbidity and mortality acting via multiple mechanisms including increased prevalence and severity of hypertension and obstructive sleep apnea (OSA). Our main thesis is that obesity exacerbates hypertension and OSA acting via increased levels of an adipocyte produced hormone leptin, a potent stimulator of the sympathetic nervous system (SNS). Hyperleptinemia is associated with hypertension and overactive hypoxic ventilatory response (HVR), which may exacerbate comorbid OSA. The progression of OSA would further aggravate hypertension. We propose a novel mechanism that leptin acts peripherally on the carotid bodies (CB) to exert SNS and HVR effects. CB are major peripheral hypoxia sensors sensitized by obesity and OSA. Our preliminary data show that (1) leptin stimulates CB via non- selective cation transient receptor potential channel melastatin 7 (TRPM7), that (2) leptin regulates HVR and this effect is abolished by TRPM7 blockers; (3) leptin induces hypertension and this effect is abolished by CSN denervation; (4) replenishment of leptin ObRb receptor in CB of leptin receptor deficient db/db mice increases Trpm7 expression and HVR exacerbating sleep apnea. Our overarching hypothesis is that leptin augments the CB chemoreflex acting via TRPM7 channels to exacerbate OSA and induce hypertension. We propose a multidisciplinary approach using electrophysiological, molecular and epigenetic techniques, as well as advance techniques for continuous recording of sleep apnea and cardiovascular variables in CB-targeted mouse models. Specific Aim 1 will determine the mechanisms by which leptin augments CB activity. We will examine whether (A) leptin signaling acutely increases TRPM7 channel activity, leading to increase in [Ca2+]i and membrane depolarization in the CB glomus cells and augmenting CB chemoreceptor response; and (B) prolonged exposure to leptin chronically upregulates Trpm7 transcription via epigenetic mechanisms. Specific Aim 2 will determine the mechanisms by which leptin affects the CB chemoreflex and sleep apnea. We will examine the effects of leptin on CB chemo reflex and sleep apnea in mice by using (A) mice with CB specific leptin ObRb receptor overexpression and knockout; and (B) mice with CB specific Trpm7 gene knockout or treated with TRPM7 inhibitors. Specific Aim 3 will determine the mechanisms by which leptin signaling in CB affects blood pressure. We will examine the effects of leptin on continuously monitored blood pressure (A) in mice with CB specific ObRb overexpression and knockout; (B) in mice with CB specific Trpm7 gene knockout and in mice treated with TRPM7 inhibitors. This project will have a significant impact by defining a novel concept of hormonal regulation of the CB functions and the pathogenesis of hypertension and sleep apnea in obesity. The successful implementation of our proposal will identify novel therapeutic targets for the treatment of hypertension and sleep apnea.